Regulatory T cells in Type 1 diabetes patients treated with IL-2

ISRCTN	ISRCTN27852285
DOI	https://doi.org/10.1186/ISRCTN27852285
ClinicalTrials.gov number	NCT01827735
Secondary identifying numbers	13846

Submission date: 26/03/2013
Registration date: 26/03/2013
Last edited: 13/10/2016

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Background and study aims
In people with Type 1 diabetes, the bodys immune system, which normally protects against infection and illness, turns around and attacks the cells of the pancreas that produce insulin. Ultimately these cells are destroyed or damaged to a point where they can no longer produce insulin. Researchers in this trial are using a drug called aldesleukin (interleukin-2) at low doses, to see if it can halt this destructive process and rebalance the immune system in people who have recently been diagnosed with Type 1 diabetes, and if so, to determine the appropriate dose needed to do so.

Who can participate?
Participants should be aged 18-50 years and have been diagnosed with Type 1 diabetes within the last two years. People with a previous medical history of organ failure, organ transplant or severe heart disease are not eligible to take part.

What does the study involve?
The study will involve a total of 12 appointments spread over about two months. Most of the visits will take place at Addenbrookes Hospital in Cambridge. During the first visit participants will provide consent and then will be screened to ensure that they are eligible to take part in the study. This will involve a series of tests including a physical exam, a chest x-ray, an electrocardiogram (a test that checks for problems with the electrical activity of your heart) and blood and urine tests. The second visit will involve further tests and then participants will receive aldesleukin (interleukin-2) as an injection just beneath the skin. To minimise the likelihood of side effects from the treatment, very low doses (about 50% less than that previously given to patients) will be used. Over the next nine weeks participants will be asked to attend 10 follow-up visits (five in the first week, two in the second week, and one each in weeks 3, 4 and 9). Each will involve further tests to monitor the participants health. During the study each participant will give a total of 400 ml of blood (less than the amount taken when donating blood).

What are the possible benefits and risks of participating?
There is no guarantee that participants in this study will benefit from taking part. The study medication may halt the destruction of insulin-producing cells in the pancreas for a short while, but the overall purpose of the study is to see whether aldesleukin (interleukin-2) could be used to benefit people with Type 1 diabetes in future by helping to protect the pancreas from damage. As with all medicines, there is a risk that participants may experience some unwanted side effects. The most common side effects reported as a result of low doses of aldesleukin are flu-like symptoms (fever, shivering, tiredness, runny nose, muscle pain and headaches), temporary soreness or redness at the point where the drug is injected and stomach upset with feelings of nausea, vomiting, abdominal pain or diarrhoea. If participants do experience these side effects, they are only likely to last a short time and will completely clear up afterwards.

Where is the study run from?
University of Cambridge and Cambridge University Hospitals Trust (UK)

When is the study starting and how long is it expected to run for?
The study started in March 2013 and ran until May 2014

Who is funding the study?
Wellcome Trust, JDRF & NIHR Cambridge Biomedical Research Centre (UK)

Who is the main contact?
Dr Frank Waldron-Lynch
Tel: 01223 762327
Email: DILT1D@cimr.cam.ac.uk
Text: DILT1D to 82727

Study website

Contact information

Dr Frank Waldron-Lynch
Scientific

JDRF/WT Diabetes & Inflammatory Laboratory
Cambridge Institute for Medical Research
University of Cambridge
WT/MRC Bldg, Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0XY
United Kingdom

Email	DILT1D@cimr.cam.ac.uk

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please email DILT1D@cimr.cam.ac.uk to request a patient information sheet
Scientific title	ADaptive study of IL-2 dose on regulatory T cells in Type 1 Diabetes (DILT1D)
Study acronym	DILT1D
Study hypothesis	Type 1 diabetes is the most common severe chronic autoimmune disease worldwide and is caused by the autoimmune (loss of self tolerance) mediated destruction of the insulin producing pancreatic beta cells thus leading to insulin deficiency and development of hyperglycaemia. Currently, medical management of type 1 diabetes focuses on intensive insulin replacement therapy to limit complications (retinopathy, nephropathy, neuropathy); nevertheless clinical outcomes remain sub optimal. There are intensive efforts to design novel immunotherapies that can arrest the autoimmune process and thereby preserve residual insulin production leading to fewer complications and better clinical outcomes. The vast majority of genes that contribute to susceptibility to type 1 diabetes have been found to encode proteins involved in immune regulation and function. In particular, several susceptibility proteins are involved in the interleukin 2 (IL-2) pathway that regulates T cell activation and tolerance to self antigens. Aldesleukin (Proleukin) is a human recombinant IL-2 product produced by recombinant DNA technology using genetically engineered E. coli stain containing an analogue of the human interleukin-2 gene. There is substantial nonclinical, preclinical and clinical data that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by induction of functional T regulatory cells. However, prior to embarking on large proof of concept trials in type 1 diabetes it is essential that the optimum dose of IL-2 is determined. The objective of this study is to establish in patients with type 1 diabetes the optimal dose of IL-2 to administer in order to increase T regulatory cell response.
Ethics approval(s)	Cambridge Central REC, First MREC approval date 18/02/2013, ref: 13/EE/0020
Condition	Topic: Diabetes Research Network; Diabetes Type 1
Intervention	Drug: Aldesleukin (Proleukin) A single, subcutaneous dose will be administered with the maximum dose allowed 1.5 X 106 IU/M2.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Aldesleukin
Primary outcome measure	T regulatory cell response; Timepoint(s): The maximum value observed in each patient's profile over the first 7 days of the follow up period.
Secondary outcome measures	No secondary outcome measures
Overall study start date	01/03/2013
Overall study end date	15/05/2014

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	50 Years
Sex	Both
Target number of participants	Planned Sample Size: 40
Participant inclusion criteria	Current inclusion criteria as of 23/08/2013: 1. Type 1 diabetes 2. 18-50 years of age 3. Duration of diabetes less than 24 months from diagnosis 4. One positive auto-antibody (anti-islet cell, anti-GAD, anti-IA2, anti-ZnT8) Previous inclusion criteria: 1. Type 1 diabetes 2. 18-50 years of age 3. Duration of diabetes more than 3 months but less than 24 months from diagnosis 4. One positive auto-antibody (anti-islet cell, anti-GAD, anti-IA2, anti-ZnT8)
Participant exclusion criteria	Current exclusion criteria as of 23/08/2013: 1. Hypersensitivity to aldesleukin or any of the excipients 2. History of severe cardiac disease 3. History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ 4. History or concurrent use of immunosuppressive agents or steroids. 5. History of unstable diabetes with recurrent hypoglycaemia 6. Active autoimmune, hyper or hypothyroidism 7. Active clinical infection 8. Major pre-existing organ dysfunction 9. Previous organ allograft 10. Females who are pregnant, lactating or intend to get pregnant during the study 11. Male who intend to father a pregnancy during the study 12. Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration 13. Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration 14. Abnormal ECG 15. Abnormal full blood count, chronic renal failure, and/or impaired liver function 16. Positive HBsAg or HepC serology or HIV test 17. Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern Previous exclusion criteria: 1. Hypersensitivity to aldesleukin or any of the excipients 2. History of severe cardiac disease 3. History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ 4. History or concurrent use of immunosuppressive agents or steroids. 5. History of unstable diabetes with recurrent hypoglycaemia 6. Hyper or hypothyroidism 7. Active clinical infection 8. Major pre-existing organ dysfunction 9. Previous organ allograft 10. Females who are pregnant, lactating or intend to get pregnant during the study 11. Male who intend to father a pregnancy during the study 12. Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration 13. Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration 14. Abnormal ECG 15. Abnormal full blood count, chronic renal failure, and/or impaired liver function 16. Positive HBsAg or HepC serology or HIV test 17. Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern
Recruitment start date	01/03/2013
Recruitment end date	15/05/2014

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Cambridge Institute for Medical Research

Cambridge
CB2 0XY
United Kingdom

Sponsor information

Cambridge University Hospitals NHS Foundation trust & University of Cambridge (UK)
Hospital/treatment centre

Research Services Department
Box 277 , Addenbrookes Hospital Hills Road
Cambridge
CB2 2QQ
England
United Kingdom

Website	http://www.cuh.org.uk/cms
"ROR"	https://ror.org/04v54gj93

Funders

Funder type

Government

Juvenile Diabetes Research Foundation
Government organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Juvenile Diabetes Research Foundation Ltd, JUVENILE DIABETES RESEARCH FOUNDATION LIMITED, JDRF UK, JDRF
Location: United Kingdom

National Institute for Health Research - Cambridge Biomedical Research Centre
Government organisation / National government

Alternative name(s): National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
Location: United Kingdom

Wellcome Trust (UK) Grant Codes: 091157/Z/10/Z
Private sector organisation / International organizations

Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	04/06/2014		Yes	No
Other publications	recruitment analysis	11/03/2015		Yes	No
Results article	results	11/10/2016		Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

13/10/2016: Publication reference added.
31/05/2016: Publication reference added.
10/06/2014: The overall trial end date was changed from 01/01/2015 to 15/05/2014.